Doxycycline targets aldehyde dehydrogenase-positive breast cancer stem cells

Targeting cancer stem cells (CSCs) is a key strategy to prevent cancers from developing drug resistance and metastasis. Mitochondria have been reported to be a vulnerability of CSCs by multiple studies. Here, we report that doxycycline, functioning as an inhibitor of mitochondrial biogenesis, can effectively target breast cancer stem cells (BCSCs). Our results revealed that doxycycline significantly decreased the frequency of aldehyde dehydrogenase-positive (ALDH(+)) BCSCs as well as mammosphere formation efficiency in HER2(+) and triple-negative breast cancer (TNBC) subtypes. Doxycycline also ameliorated paclitaxel-induced enrichment of ALDH(+) BCSCs in TNBC. Mechanistically, we showed that doxycycline decreased the level of reactive oxygen species and their downstream p38 MAPK pathway. In agreement with the key role for p38 in maintaining BCSCs, a specific inhibitor targeting this MAPK pathway significantly decreased the number of ALDH(+) cells. Doxycycline is a FDA-approved drug with minor and limited side-effects. Given doxycycline's low toxicity and strong effect on BCSC inhibition, we report that doxycycline should be safe to be used concomitantly with chemotherapy drugs to eradicate both CSCs and bulk tumor cells.